Thrombopoietin (TPO) is a cytokine that stimulates the proliferation and differentiation of megakaryocytes, the precursors to blood platelets. Recombinant human TPO is a promising treatment for stimulating platelet production in patients with thrombocytopenia resulting from myelosuppressive chemotherapy. We propose to create modified TPO proteins that are equal or superior to natural TPO at stimulating platelet formation in vivo, but which require less frequent dosing, on the order of once per week to once every third week. Optimally, the compound could be administered once per chemotherapy cycle. During Phase I we will identify sites in TPO that can be modified without affecting the protein's in vitro bioactivity. During Phase II, we will manufacture sufficient quantities of the modified TPO proteins for testing in animal models of thrombocytopenia. The improved characteristics of the novel TPO proteins will reduce the amount of TPO required per patient, improve patient compliance and quality of life and result in considerable cost savings to patients and healthcare providers. These proteins will find utility in treating thrombocytopenia resulting from myelosuppressive chemotherapy and drug complications. Information gained from these studies will aid in creating long-acting versions of structurally related cytokines and growth factors for use in treating cancer, infectious disease and hematopoietic disorders. PROPOSED COMMERCIAL APPLICATIONS: The long-acting TPO proteins under development potentially can be used to restore platelet production in patients with thrombocytopenia resulting from chemotherapy. The U.S. market for platelet-stimulating agents is estimated to be in excess of $300 million. These modified TPO proteins will require much less frequent dosing than existing products, providing significant cost savings to patients and healthcare providers. Additional expected benefits include improved drug efficacy, reduced toxicity and improved patient quality of life.